The long-term objective of this Patient-Oriented Mentored Research Career Development Award (K23) is to support the development of the candidate as an investigator in translational neuroscience of mood disorders. This will be accomplished through a structured, supervised research experience along with formal didactic instruction focused on (1) Clinical Research Methodology (including MRS Methods, Data Analysis, Biostatistics, and Ethics) and (2) Affective Neuroscience. Major depressive disorder (MDD) is a serious public health concern associated with significant morbidity and mortality. The identification of neurobiological correlates of major depressive disorder (MDD) has been hampered by the disorder's heterogeneity. To address this challenge, the proposed project utilizes a dimensional investigative approach focusing on anhedonia - the loss of pleasure - a core symptom of MDD that is associated with suicide and less favorable prognosis. Anhedonia manifests a full range of severity and is fundamentally related to the neural reward circuitry. Our team reported strong associations between peripheral inflammation, known to induce oxidative stress (OS), and anhedonia severity in humans. Using proton magnetic resonance spectroscopy (1H MRS) we found positive correlations between peripheral inflammation and striatal total choline (membrane turnover biomarker) in anhedonic patients. More recently, our team reported decreased glutathione (GSH, the most important brain antioxidant) in MDD, as well as negative associations between brain GSH and anhedonia severity. Building upon these promising preliminary data, the proposed study will test the overall hypothesis that inflammation-mediated changes in GSH and OS are specifically linked to MDD and anhedonia severity. We will enroll 50 psychotropic-medication free subjects with MDD and 25 matched healthy controls, ages 21-65. The study will consist of a comprehensive, systematic diagnostic procedure that includes structured dimensional assessments of anhedonia. We will measure concentrations of GSH in the anterior cingulate cortex and striatum, regions of the neural reward circuitry, using 1H MRS, along with plasma levels of cytokines and OS markers. RELEVANCE AND IMPACT: To address the heterogeneous nature of MDD, the proposed research focuses on the well-quantified phenotype of anhedonia while employing an integrated investigative strategy of immunological and neurochemical imaging. The proposed research can lead to more mechanistic, neuroscience-based understanding (consistent with the NIH RDoC initiative) of this severe psychiatric disorder. The results of this study will also validate inflammation and OS as bona fide disease biomarkers and potential treatment targets, ultimately leading to clinical trials of novel interventions in humans. Importantly, the skills and data acquired during the K23 award period will provide the candidate with the tools required to achieve the long-term goal of becoming an independent investigator in translational neuroscience research of mood disorders.